The goals of this research program are to enhance the prevention and improve the management of fecal incontinence (FI) in women by clarifying the risk factors and mechanisms for this disorder using multidisciplinary, innovative approaches. While current concepts emphasize the role of anal sphincter weakness, our epidemiological and mechanistic studies strongly support the hypothesis that FI is caused by complex of recto-anal sensorimotor dysfunctions rather than isolated anal dysfunction. Our specific aims are to assess the hypotheses that: (i) The rectum is stiffer in women who have had a hysterectomy and also in women with urge FI;(iia) Partially reversible rectal motor dysfunctions predominantly due to neurogenic rather than myogenic mechanisms contribute to rectal hypersensitivity in women with urge FI;(iib) denervation supersensitivity contributes to increased rectal stiffness after a hysterectomy;and (iii) clonidine will restore rectal sensorimotor functions and thereby improve symptoms in FI. Our corresponding aims are to (i) measure overall and regional rectal stress:strain relationships by simultaneous MRI during rectal balloon distention in 24 asymptomatic women and in 24 women with urge FI, also controlling for hysterectomy;(iia) compare the acute effects of atropine and nifedipine on rectal mechanical properties (i.e., compliance, capacity, and the phasic response to distention) and rectal perception of distention in 56 women with and 36 women without urge FI, also controlling for hysterectomy;(iib) assess the effects of a cholinergic agonist on rectal sensorimotor in 24 women who have or have not had a hysterectomy;and (iii) study the effects of clonidine on symptoms and rectal sensorimotor functions in a double- blind placebo-controlled study of 40 women with FI. By testing mechanistic hypotheses which are integrated with a new therapy, these studies are poised to fundamentally alter our understanding and management of FI in women. Public Health Relevance: Fecal incontinence (FI) affects 10% of all and up to 20% of postmenopausal women. FI can cause significant distress, impair daily functioning, and contribute to institutionalization. The pathophysiology of FI is poorly understood, while available therapeutic options are limited, not evidence-based, and primarily focus on improving anal sphincter function. This proposal will enhance our understanding of the mechanisms and assess novel approaches to manage FI.